The present invention is directed to a process for producing 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one. In particular, the present invention is directed to an enantioselective process for producing the same.
xcex4-Lactones such as 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-ones are useful intermediates in the preparation of a variety of fine chemicals and pharmaceutically active compounds. For example, 5,6-dihydro-3-hexyl-4-hydroxy-6-undecyl-pyran-2-one is a well known precursor for the preparation of oxetanones such as tetrahydrolipstatin. See for example, U.S. Pat. Nos. 5,245,056 and 5,399,720, both issued to Karpf et al.; and U.S. Pat. Nos. 5,274,143 and 5,420,305, both issued to Ramig et al.
Other methods of preparing tetrahydrolipstatin use a xcex2-hydroxy ester, e.g., methyl 3-hydroxy tetradecanoate, as an intermediate. See for example, Pommier et al., Synthesis, 1994, 1294-1300, Case-Green et al., Synlett., 1991, 781-782, Schmid et al., Proceedings of the Chiral Europe ""94 Symposium, Sep. 19-20, 1994, Nice, France, and the above mentioned U.S. Patents. Some methods of preparing oxetanones, such as those disclosed in the above mentioned U.S. Patents issued to Karpf et al., use a xcex2-hydroxy ester as an intermediate to prepare the xcex4-lactone which is then used in the synthesis of oxetanones.
The stereochemistry of a molecule is important in many of the properties of the molecule. For example, it is well known that physiological properties of drugs having one or more chiral centers, i.e., stereochemical centers, may depend on the stereochemistry of a drug""s chiral center(s). Thus, it is advantageous to be able to control the stereochemistry of a chemical reaction.
Many oxetanones, e.g., tetrahydrolipstatin, contain one or more chiral centers. Intermediates xcex4-lactone and xcex2-hydroxy ester used in the synthesis of tetrahydrolipstatin contain one chiral center. Some syntheses of these intermediates, such as those disclosed in the above mentioned U.S. Patents issued to Karpf et al., are directed to the preparation of a racemic mixture which is then resolved at a later step to isolate the desired isomer. Other methods are directed to an asymmetric synthesis of xcex2-hydroxy ester by enantioselectively reducing the corresponding xcex2-ketoester.
Moreover, in order to achieve a high yield of the desired product, some current asymmetric hydrogenation processes for reducing methyl 3-oxo-tetradecanoate require extremely pure reaction conditions, e.g., hydrogen gas purity of at least 99.99%, thus further increasing the cost of producing the corresponding xcex2-hydroxy ester.
Therefore, there is a need for a process for producing xcex4-lactones. And there is a need for enantioselectively reducing xcex2-ketoesters under conditions which do not require extremely pure reaction conditions or high hydrogen gas pressure.
One embodiment of the present invention provides a process for the preparation of a xcex4-lactone of the formula: 
comprising:
(a) treating an acyl halide of the formula: 
xe2x80x83with a ketene acetal of the formula: 
xe2x80x83under conditions sufficient to produce a coupled intermediate product; and
(b) providing conditions sufficient to produce the xcex4-lactone I from the coupled intermediate product, where R1 is C1-C20 alkyl; R2 is H or C1-C10 alkyl; R3 is a hydroxy protecting group; each of R4 and R5 is independently C1-C6 alkyl, C5-C20 aryl, C6-C20 arylalkyl or xe2x80x94SiR8R9R10; each of R8, R9, R10 is independently C1-C6 alkyl or phenyl; and X is,a halide.
The coupled product can be xe2x80x9ctrappedxe2x80x9d (i.e., reacted) with a protecting group to produce an enol ether compound. Without being bound by any theory, it is believed that the coupled product or the enol ether compound is xcex4-hydroxy-xcex2-enol ether ester or xcex4-hydroxy-protected-xcex2-enol ether ester of the formula: 
where R6 is H or R4, and R1, R2, R3, R4, and R5 are those defined above. It should be appreciated that while Compound IV is depicted with the double bond in the xcex2,xcex3-position, it can also exist with the double bond in the xcex1,xcex2-position. Moreover, the double bond can be either E- or Z-configuration. Thus, when referring to Compound IV, it is intended that these isomers, or mixtures thereof are also within the scope of the present invention.
Where R6 of the coupled intermediate product (i.e., Compound IV) is not hydrogen (i.e., R6 is a hydroxy protecting group), the step (b) above can include the steps of removing (i.e., deprotecting) R6 or R3 and R6 to produce a deprotected intermediate, and contacting the deprotected intermediate with an acid under conditions sufficient to produce the xcex4-lactone I.
Another embodiment of the present invention provides a process for the preparation of the xcex4-lactone I comprising the steps of:
(a) treating an acyl halide of the formula: 
xe2x80x83with a malonate half acid of the formula: 
xe2x80x83under conditions sufficient to produce a xcex4-hydroxy-xcex2-ketoester of the formula: 
xe2x80x83and
(b) contacting the xcex4-hydroxy-protected-xcex2-enol ether ester VI with an acid under conditions sufficient to produce the xcex4-lactone I, where R1, R2, R3, R5, and X are those described above, and R7 is H or R3.
Because Compound VII contains acidic group, it may exist in its enol (i.e., tautomeric) form under certain conditions. Thus, any reference to the Compound VII implicitly includes its tautomeric form.
Preferably, methods of the present invention provide an enantioselective synthesis of the xcex4-lactone I.
Another embodiment of the present invention provides a process for enantioselective preparation of a xcex2-hydroxy ester of the formula: 
comprising hydrogenating a xcex2-ketoester of the formula: 
in the presence of about 40 bar of pressure or less of hydrogen gas and a ruthenium hydrogenation catalyst comprising a halide and a chiral substituted biphenyl phosphorous ligand, where R1 is that described above, and R18 is C1-C6 alkyl, C5-C20 aryl or C6-C20 arylalkyl.
Still another embodiment of the present invention provides compound selected from the group consisting of xcex2-siloxy acyl halides of the formula: 
xcex4-siloxy-xcex2-silyl enol ether esters of the formula: 
and xcex4-siloxy-xcex2-ketoesters of the formula: 
where R1, R2, R5, R8, R9, R10, and X are those described above, and each of R11, R12 and R13 is independently C1-C6 alkyl or phenyl.
Similar to Compound IV, Compound XI can also exist in different olefin geometry (i.e., E- or Z- isomers) and/or different double bond location (i.e., in the xcex1,xcex2-position instead of in the xcex2,xcex3-position as depicted). Thus, while Compound XI is depicted as that shown above, it is intended that the scope of the present invention includes these isomers of Compound XI.
As used herein, the term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ccontactingxe2x80x9d or xe2x80x9creactingxe2x80x9d refers to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
The term xe2x80x9calkylxe2x80x9d refers to aliphatic hydrocarbons which can be straight or branched chain groups. Alkyl groups optionally can be substituted with one or more substituents, such as a halogen, alkenyl, alkynyl, aryl, hydroxy, amino, thio, alkoxy, carboxy, oxo or cycloalkyl. There may be optionally inserted along the alkyl group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms. Exemplary alkyl groups include methyl, ethyl, i-propyl, n-butyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, trichloromethyl, pentyl, hexyl, heptyl, octyl, decyl and undecyl.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic carbocyclic or heterocyclic aromatic ring moieties. Aryl groups can be substituted with one or more substituents, such as a halogen, alkenyl, alkyl, alkynyl, hydroxy, amino, thio, alkoxy or cycloalkyl. Exemplary aryl groups include phenyl, toluyl, pyrrolyl, thiophenyl, furanyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl.
The present invention provides a process for the preparation of 6-lactones, such as 3,6-dialkyl-5,6-dihydro-4-hydroxy-2H-pyran-2-ones. In particular, the present invention provides a process for the preparation of a xcex4-lactone of the formula: 
where R1 is C1-C20 alkyl, and R2 is H or C1-C10 alkyl. In particular, the present invention provides a process for enantioselectively producing the xcex4-lactone I. In one specific embodiment of the present invention, the enantioselective process provides (R)-xcex4-lactone I having the following stereocenter: 
It should be appreciated that the xcex4-lactone of formula I and the corresponding enantiomerically enriched xcex4-lactone IA may also exist in, or are in equilibrium with, their tautomeric forms: 
respectively. Therefore, any reference to the xcex4-lactone of formula I or IA implicitly includes its tautomeric form of formula IB or IC, respectively.
The present invention will now be described in reference to the synthesis of enantiomerically enriched xcex4-lactone IA. It should be appreciated that the racemic form of xcex4-lactone I or xcex4-lactone having the opposite stereochemical configuration as that of formula IA, while not explicitly discussed herein, can be readily prepared using the processes of the present invention by using a racemic mixture or opposite stereochemically configured starting materials, respectively.
In one embodiment of the process of the present invention, the process includes treating an acyl halide of the formula: 
with a ketene acetal of the formula: 
under conditions sufficient to produce a xcex4-hydroxy-protected-xcex2-enol ether ester of the formula: 
where R1 and R2 are described above; R3 is a hydroxy protecting group; each of R4 and R5 is independently C1-C6 alkyl, C5-C20 aryl (preferably C6-C20 aryl), C6-C20 arylalkyl (preferably C7-C20 arylalkyl) or a moiety of the formula xe2x80x94SiR8R9R10; R6 is H or R4; X is halide, preferably chloride; and each of R8, R9 and R10 is independently C1-C6 alkyl or phenyl.
A variety of protecting groups, including protecting groups for hydroxy and carboxylic acid functional groups, are known in the art, and can be employed. Examples of many of the possible protecting groups can be found in Protective Groups in Organic Synthesis, 3rd edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, New York, 1999, which is incorporated herein by reference in its entirety.
With reference to compounds I-IVA above:
Preferably, R1 is undecyl.
Preferably, R2 is C1-C10 alkyl, more preferably hexyl.
Preferably, R3 is a moiety of the formula xe2x80x94SiR11R12R13, where each of R11, R12 and R13 is independently C1-C6 alkyl or phenyl, more preferably each of R11, R12 and R13 is independently methyl, isopropyl, tert-butyl or phenyl. More preferably R3 is a moiety of the formula xe2x80x94Si(CH3)3.
Preferably, R4 is a moiety of the formula xe2x80x94SiR8R9R10. Preferably each of R8, R9 and R10 is independently methyl, isopropyl, tert-butyl or phenyl. More preferably R4 is a moiety of the formula xe2x80x94Si(CH3)3.
Preferably, R5 is C1-C6 alkyl, C5-C20 aryl or C6-C20 arylalkyl. More preferably R5 is C1-C6 alkyl. Still more preferably R5 is methyl or ethyl.
Preferably, R6 of compound V is same as R4 of compound IV, particularly when R4 is a moiety of the formula xe2x80x94SiR8R9R10.
Processes of the present invention also include treating xcex4-hydroxy-protected-xcex2-enol ether ester IVA under reaction conditions sufficient to remove at least one of the protecting groups (i.e., R6 or R3 and R6) and contacting the resulting deprotected compound with an acid to produce the xcex4-lactone I.
A particularly useful ketene acetal III is a silyl ketene acetal in which R4 is a moiety of the formula xe2x80x94SiR8R9R10 and R5 is C1-C6 alkyl, C5-C20 aryl or C6-C20 arylalkyl. Silyl ketenes can be readily prepared by any of the currently known methods. Some of the methods for preparing silyl ketenes are disclosed in Miura et al., Bull. Chem. Soc. Jpn., 1991, 64, 1542-1553; Umemoto and Gotoh, Bull Chem. Soc. Jpn., 1987, 60, 3823-3825; Sugimoto et al., Chem. Lett., 1991, 1319-1322; Miura et al., Bull. Chem. Soc. Jpn., 1992, 65, 1513-1521; and Shono et al., J. Org. Chem., 1984, 49, 1056-1059, which are incorporated herein by reference in their entireties.
The silyl ketene acetal III can be prepared from the corresponding ester (i.e., a compound of the formula R2xe2x80x94CH2xe2x80x94C(xe2x95x90O)OR5) by treating the ester with a strong base such as lithium hexamethyldisilazide (LiHMDS), a dialkylamide, e.g., lithium diisopropylamide and lithium tetramethylpiperidine (LiTMP), in a conventional aprotic organic solvent, such as tetrahydrofuran (THF), hexane, dimethoxy ethane (DME), ether or mixtures thereof, to generate an enolate and trapping (i.e., contacting) the enolate with a silylating agent, including a silyl triflate and silyl halide, such as silyl chloride, e.g., trimethylsilyl chloride. Dialkylamide can be prepared by treating the corresponding dialkylamine with a strong base, such as an alkyllithium (e.g., butyllithium) in a conventional aprotic organic solvent described above. The preparation of silyl ketene acetal III is generally carried out under preferably an inert atmosphere such as nitrogen, argon, or the like, at a temperature preferably at or less than about 0xc2x0 C., more preferably at or less than about xe2x88x9230xc2x0 C., and most preferably at about xe2x88x9278xc2x0 C. The silyl ketene acetal III can be purified, e.g., by distillation under a reduced pressure. When R2 is C1-C10 alkyl and R4 and R5 are different moieties, the resulting silyl ketene acetal III can have two different geometric isomers, i.e., E- or Z-double bond configuration. It should be appreciated that since the carbon atom of xcex4-lactone I containing R2 group can be readily isomerized, the geometric isomer of the silyl ketene acetal III is not important for enantioselective processes of the present invention.
In one particular embodiment of the present invention, the xcex4-hydroxy-protected-xcex2-enol ether ester IVA, where R6 is R4, is prepared by reacting the above described silyl ketene acetal III with the acyl halide IIA, where R3 is a moiety of the formula xe2x80x94SiR11R12R13. The reaction is typically carried out in a conventional aprotic organic solvent, such as THF, toluene, heptane, hexane or mixtures thereof, in the presence of a tertiary amine including trialkylamine, such as triethylamine or tributylamine, under preferably an inert atmosphere described above. Preferably, the reaction temperature is in the range of from about 0xc2x0 C. to about 25xc2x0 C.
The crude xcex4-hydroxy-protected-xcex2-enol ether ester IVA can be purified, e.g., by distillation under a reduced pressure or by chromatography, or it can be used directly in the next step without any purification. As used herein, a xe2x80x9ccrudexe2x80x9d compound refers to a compound which is not subject to a separate purification step other than a conventional work-up of the reaction.
The resulting xcex4-hydroxy-protected-xcex2-enol ether ester IVA, in particular where R3 and R6 are a moiety of the formula xe2x80x94SiR11R12R13 and xe2x80x94SiR8R9R10, respectively, can be selectively monodesilylated to produce a xcex4-siloxy-xcex2-ketoester of the formula: 
under acidic or basic conditions, preferably under basic conditions. For basic monodesilylation conditions, typically a tertiary amine including a trialkylamine, such as triethylamine or preferably tributylamine; or a bicarbonate, such as potassium bicarbonate, lithium bicarbonate or preferably sodium bicarbonate, is used. The monodesilylation reaction can be conducted in a protic solvent, such as alkyl alcohol (e.g., methanol, ethanol and isopropanol), or a mixture of aprotic organic solvent and a protic solvent (e.g., alkyl alcohol or water). Exemplary aprotic organic solvents which are useful in monodesilylation reaction include methylene chloride, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), THF and ethyl ether. Preferably, the monodesilylation reaction is carried out in an alkyl alcohol solvent, more preferably in methanol. The monodesilylation reaction temperature range is preferably from about 0xc2x0 C. to about 25xc2x0 C.
The xcex4-siloxy-xcex2-ketoester VIA can be further desilylated under acidic or basic conditions, preferably under acidic conditions, and cyclized to produce the xcex4-lactone I. Desilylation of a hydroxy group is well known to one of ordinary skill in the art and is disclosed in the above mentioned Protective Groups in Organic Synthesis. For acidic desilylation conditions, typically an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, or trifluoroacetic acid is used. Desilylation of the xcex4-siloxy-xcex2-ketoester VIA under an acidic condition results in a rapid cyclization to produce the xcex4-lactone I, thus eliminating a need for a separate cyclization step.
Alternatively, the xcex4-lactone I can be produced by removing both of the protecting groups (R3 and R6) from the xcex4-hydroxy-protected-xcex2-enol ether ester IVA in a single step and contacting the deprotected product with an acid under conditions sufficient to produce the xcex4-lactone I. As used herein, the term xe2x80x9csingle stepxe2x80x9d refers to removal of both protecting groups R3 and R6 under same reaction conditions. In a particular embodiment of the present invention, where R3 and R6 of xcex4-hydroxy-protected-xcex2-enol ether ester IVA are moieties of the formula xe2x80x94SiR11R12R13 and xe2x80x94SiR8R9R10, respectively, it is preferred that both of the silyl groups are removed in a single step under a basic condition, typically using a hydroxide or preferably a carbonate. Exemplary hydroxides which can be used in the present invention include sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide. Exemplary carbonates which are useful in the present invention include potassium carbonate, lithium carbonate, sodium carbonate and cesium carbonate. Preferred carbonate is potassium carbonate. A single step removal of both silyl groups can be carried out in a same solvent as those described above for monodesilylation. The reaction temperature range of a single step desilylation and subsequent production of the xcex4-lactone I is preferably from about 0xc2x0 C. to about 25xc2x0 C.
Typically, the xcex4-lactone I is produced by adjusting the pH of the reaction mixture to from about pH 3 to about pH 5. Any acid which is capable of providing the above described pH range of the reaction mixture may be used, such acids include, but are not limited to, hydrochloric acid, sulfuric acid, and phosphoric acid. In one particular embodiment of the present invention, hydrochloric acid is used to produce the xcex4-lactone. The xcex4-lactone I thus formed typically precipitates from the reaction mixture, e.g., when methanol is used as the solvent. The xcex4-lactone I can be further purified, e.g., by recrystallization, to obtain higher purity and/or higher enantiomeric excess of xcex4-lactone I.
In another embodiment of the present invention, the acyl halide IIA is treated with a malonate half acid of the formula: 
under conditions sufficient to produce a xcex4-hydroxy-xcex2-ketoester of the formula: 
where R1, R2 and R5 are described above, and R7 is H or R3. Preferably, R7 is H.
The process of the present invention also includes contacting the xcex4-hydroxy-xcex2-ketoester VIA with a base or preferably an acid under conditions sufficient to produce the xcex4-lactone I, as described above.
The reaction between the acyl halide IIA and the malonate half acid V is typically carried out in the presence of a metal coordinating agent and a tertiary amine base. See for example, Rathke and Cowan, J. Org. Chem., 1985, 50, 2622-2624, and Clay et al., Synthesis, 1993, 290-292, which are incorporated herein by reference in their entirety. The reaction can be conducted under an aprotic organic solvent, such as n-butyl ether, THF, acetonitrile, methylene chloride, dimethoxyethane (DME), methyl t-butyl ether (MTBE), toluene, 2-methyltetrahydrofuran (2-Mexe2x80x94THF), with THF being the preferred solvent. Without being bound by any theory, it is believed that the use of a metal coordinating agent generates a metal enolate of the malonate half acid V, which is sufficiently reactive to react with the acyl halide IIA, but is not basic enough to deprotonate the initially formed product, which contains an acidic proton.
In general, the reaction between the acyl halide IIA and the malonate half acid V is conducted by adding the acyl halide IIA, preferably in a solution, to a solution mixture which includes the malonate half acid V, the metal coordinating agent and the tertiary amine base. Higher yield of the xcex4-hydroxy-xcex2-ketoester VIA can be obtained by using at least about 2 equiv. of a relatively non-nucleophilic base, such as a tertiary amine, and at least 1 equiv. of the metal coordinating agent relative to the amount of malonate half acid V.
Exemplary metal coordinating agents include magnesium salts including magnesium halides, such as MgCl2, MgBr2 and MgI2; manganese salts, such as manganese halides and manganese acetates; lithium salts, such as lithium halides; samarium salts, such as samarium halides; and mixtures of sodium and lithium salts, such as mixtures of sodium halides and lithium halides. Preferably, the metal coordinating agent is a magnesium salt, more preferably magnesium chloride.
Exemplary tertiary amine bases which are useful in the present invention include trialkylamines, such as triethylamine, diethylisopropylamine and tributylamine. Preferably, the tertiary amine base is a trialkylamine, more preferably triethylamine, diethylisopropylamine or tributylamine.
Typically, the reaction between the acyl halide IIA and the malonate half acid V is conducted at a temperature ranging from about 0xc2x0 C. to about 35xc2x0 C., under preferably an inert atmosphere as those described above. Preferably, the reaction is conducted at about 25xc2x0 C.
The resulting xcex4-hydroxy-xcex2-ketoester VIA can be isolated or preferably used directly without isolation and treated with an acid under conditions sufficient to produce the xcex4-lactone I. For example, after reacting the acyl halide IIA with the malonate half acid V, an acid described above is added to the resulting reaction mixture, which results in the formation of the xcex4-lactone I.
Preferably, alkyl malonate half acid V is methyl or ethyl malonate half acid V, where R5 is methyl or ethyl, as the methyl or ethyl xcex4-hydroxy-xcex2-ketoester VIA produces the xcex4-lactone I in higher yield than other malonate half acid V under similar reaction conditions and time. One can take advantage of this higher yield by methyl or ethyl malonate half acid V by converting a non-methyl or non-ethyl malonate half acid V to methyl or methyl malonate half acid V, and then reacting the methyl or ethyl malonate half acid V with the acyl halide IIA to produce the xcex4-lactone I. For example, propyl malonate half acid V, where R5is propyl, can be reacted with a metal methoxide, such as sodium methoxide, in methanol under conditions sufficient to produce the methyl malonate half acid V from propyl malonate half acid V, and then reacting the resulting methyl malonate half acid V with acyl halide IIA to produce the xcex4-lactone I. Alternatively, the product of a reaction between non-methyl malonate half acid V and the acyl halide IIA can be converted to its corresponding methyl xcex4-hydroxy-xcex2-ketoester VIA prior to contacting with an acid or preferably in situ during the cyclization step to produce the xcex4-lactone I.
The malonate half acid V, where R2 is not H, can be prepared by a variety of methods. For example, malonate half acid V can be prepared by treating malonate diester, e.g., R5OC(xe2x95x90O)CH2C(xe2x95x90O)OR5, with a base, such as sodium ethoxide, to generate the corresponding enolate and contacting the enolate with an alkyl group containing a leaving group, for example, mesylate, tosylate and halides such as bromide and iodide, to produce an alkyl malonate diester, i.e., R5OC(xe2x95x90O)CH(R2)C(xe2x95x90O)OR5. The alkyl malonate diester is then monosaponified, typically using less than about I equiv., preferably about 0.9 equiv. of hydroxide in the corresponding R5 alcohol solvent to produce the malonate half acid V, for example, by treating with a hydroxide, such as potassium hydroxide, sodium hydroxide or lithium hydroxide, in methanol (when R5 is methyl) or ethanol (when R5 is ethyl).
Processes of the present invention can also include the step of producing the acyl halide IIA from a xcex2-hydroxy acid or salts thereof, such as potassium or sodium salts, of the formula: 
by protecting the hydroxy group to produce a xcex2-hydroxy-protected ester of the formula: 
and contacting the xcex2-hydroxy-protected ester XIV with an acyl halogenating agent under conditions sufficient to produce the acyl halide IIA, where R1 and R3 are described above and R14 is H, R3 or a carboxylate counter cation. As used herein, the term xe2x80x9ccarboxylate counter cationxe2x80x9d refers to a counter ion of the carboxylic salt of formula XIV. Exemplary carboxylate counter cations include metal cations, such as sodium, lithium and potassium; ammonium; mono-, di-, tri- and tetraalkylammonium; pyridinium; and other suitable cations for carboxylic anions which are known to one of ordinary skill in the art.
In one particular embodiment of the present invention, the acyl halide IIA is produced by contacting the xcex2-hydroxy acid XIII with a silylating agent to produce a xcex2-silyloxy silyl ester of the formula: 
and contacting the xcex2-silyloxy silyl ester XV with an acyl halogenating agent, where R11, R12 and R13 are those described above. Any hydroxy silylating agent known in the art can be used to produce the xcex2-silyloxy silyl ester XV. Exemplary silylating agents include compounds of the formula X1xe2x80x94SiR11R12R13, where R11, R12 and R13 are described above and X1 is a halide or triflate; and hexamethyldisilazane (when R11, R12 and R13 are methyl).
For example, xcex2-trimethylsiloxy trimethyl silyl ester of compound XV, where R11, R12 and R13 are methyl, can be prepared by treating the xcex2-hydroxy acid with chlorotrimethylsilane (TMSCl) in the presence of pyridine preferably under an inert atmosphere described above. The reaction is preferable conducted in an aprotic organic solvent such as methylene chloride, MTBE, toluene and THF, with THF being a particularly preferred solvent. The temperature range of the reaction is generally from about 0xc2x0 C. to about 25xc2x0 C., preferably the reaction temperature is about 25xc2x0 C. The reaction can also include 4-dimethylaminopyridine (DMAP) or other silylating catalyst known to one of ordinary skill in the art. When a silylating catalyst such as DMAP is present, it is typically used at about 1 mole %. Even without the presence of a silylating catalyst, silylation is typically complete within few hours, generally within about 2 hours at room temperature.
Alternatively, the xcex2-trimethylsiloxy trimethyl silyl ester XV can be prepared by using hexamethyldisilazane (HMDS). For example, heating a mixture of xcex2-hydroxy acid XIII and HMDS in an aprotic organic solvent, such as toluene or preferably THF, produces the xcex2-trimethylsiloxy trimethyl silyl ester XV. When HMDS is used, one of the by-products of the reaction is ammonia, which can be readily removed by partially distilling the reaction solvent typically at atmospheric pressure. The resulting partially concentrated solution of xcex2-trimethylsiloxy trimethyl silyl ester XV can be used directly in the acyl halide IIA producing step without further purification.
A variety of acyl halogenating agents are known to one of ordinary skill in the art. Exemplary acyl halogenating agents and general procedures for using the same are disclosed, for example, in xe2x80x9cComprehensive Organic Synthesis,xe2x80x9d vol. 6, Trost, Fleming and Winterfeldt eds., Pergamon Press, 1991, pp. 301-319, and xe2x80x9cThe Chemistry of Acyl Halides,xe2x80x9d Patai, ed., Interscience Publishers, 1972, pp. 35-64, which are incorporated herein by reference in their entireties. It has been found by the present inventors that xcex2-hydroxy-protected ester XIV, in particular xcex2-trimethylsiloxy trimethyl silyl ester XV, can be readily converted to the acyl halide IIA using oxalyl chloride or thionyl chloride in an aprotic organic solvent, such as toluene or preferably THF.
When using oxalyl chloride as the acyl halogenating agent, pyridine and a catalytic amount of silylating catalyst such as DMF is typically used. However, when thionyl chloride is used as the acyl halogenating agent in place of oxalyl chloride, a need for using a silylating catalyst such as DMF is eliminated. In either case, formation of pyridinium salts in an acyl halogenation reaction may complicate the reaction between the ketene acetal III and the acyl halide IIA. To avoid possible complications in the reaction between the ketene acetal III and the acyl halide IIA, typically pyridinium salts are removed from the reaction mixture, e.g., by filtration. The resulting reaction mixture is then further concentrated, e.g., by distillation, which also removes at least a portion of any residual TMSCl, thionyl chloride and THF. The distillation is generally conducted under a reduced pressure at about 0xc2x0 C.
It has been found by the present inventors that when HMDS is used as the silylating agent for xcex2-hydroxy acid XIII in THF, the subsequent acyl halogenation reaction with thionyl chloride in THF is slow at 0xc2x0 C. and gives poor yields at higher reaction temperatures. However, a presence of pyridinium salts, such as pyridinium hydrochloride, pyridine or DMAP increases the reaction rate and yields higher amounts of the desired acyl halide IIA. Thus, when HMDS is used as the silylating agent, pyridine is typically added to the subsequent acyl halogenation reaction. The amount of pyridine added is generally from about 1 mole % to about 10 mole %, and preferably about 2 mole %. The halogenation reaction is conducted at a reaction temperature of typically about 0xc2x0 C.
Processes of the present invention can also include enantioselective preparation of xcex2-hydroxy acid XIII from a xcex2-ketoester of the formula: 
by enantioselectively reducing the ketone carbonyl of the xcex2-ketoester XVI and saponifying the ester group to produce the xcex2-hydroxy acid XIII, where R1 is described above and R18 is C1-C6 alkyl, C5-C20 aryl or C6-C20 arylalkyl. Preferably R18 is C1-C6 alkyl, more preferably methyl or ethyl.
In one particular embodiment of the present invention, an enantioselective preparation of xcex2-hydroxy ester XIII involves hydrogenation of the xcex2-ketoester XVI in the presence of a chiral hydrogenation catalyst. It should be appreciated that an achiral hydrogenation catalyst will result in racemic mixture of xcex2-hydroxy ester XIII, and a chiral hydrogenation catalyst having an opposite configuration as those described below will result in xcex2-hydroxy ester having an opposite configuration as that shown in Figure XIII. Specifically, the present invention provides a process for enantioselectively reducing the xcex2-ketoester XVI using an enantiomerically enriched hydrogenation catalyst, i.e., hydrogenation catalyst having greater than about 97% enantiomeric excess (%ee).
In one particular embodiment of the present invention, the chiral hydrogenation catalyst comprises a ruthenium catalyst containing a chiral ligand such as those shown in the Examples section, including a catalyst of the formula: 
where X2 is a halide, such as iodide, bromide or preferably chloride, and each of R19 and R20 is independently H, C1-C6 alkyl or C1-C6 alkoxy, provided at least one of R19 or R20 is not H. Moreover, each phenyl group may contain more than one R19 or R20 groups. Furthermore, one or both of the phenyl groups of the biphenyl moiety may be replaced with other aromatic groups such as a naphthyl, pyridyl or other substituted aryl groups.
One of the useful hydrogenation catalyst of the present invention is a product produced by contacting a ruthenium diacetate of the formula Ru(OAc)2((R)-MeOBIPHEP) with a halide source, such as alkaline metal halides (e.g., LiX, NaX, KX and CsX, where X is a halide) or hydrohalides (e.g., HX, where X is a halide), preferably hydrochloric acid, where Ru(OAc)2((R)-MeOBIPHEP) is a compound of the formula: 
Without being bound by any theory, it is believed that treating Ru(OAc)2((R)-MeOBIPHEP) with hydrochloric acid results in replacing both of the OAc groups with chloride; thus, the resulting product is believed to be Ru(Cl)2((R)-MeOBIPHEP). Interestingly, however, when Ru(OAc)2((R)-MeOBIPHEP) is treated with less than about 2 equiv. of HCl, the resulting hydrogenation catalyst does not produce (R)-3-hydroxy ester XIII in a high enantiomeric excess. Surprisingly and unexpectedly, in some cases such a hydrogenation catalyst produces (S)-3-hydroxy ester predominantly. However, when at least about 5 equiv. of HCl is added to Ru(OAc)2((R)-MeOBIPHEP), preferably at least about 10 equiv. and more preferably at least about 20 equiv., the resulting hydrogenation catalyst enantioselectively reduces the xcex2-ketoester XVI to the corresponding (3R)-3-hydroxy ester.
The precursor of chiral hydrogenation catalyst of the present invention, i.e., ruthenium dicarboxylate diphosphine compound or [Ru(OC(xe2x95x90O)Rxe2x80x2)2(diphosphine)], can be prepared according the following reaction scheme: 
In this manner a variety of chiral ruthenium dicarboxylate diphosphines, including those listed in Example 16, can be prepared. The process for preparing a ruthenium dicarboxylate diphosphine compound generally involves contacting [RuCl2(COD)]n, which is commercially available or preferably prepared according to the procedure of Albers et al., Inorg. Synth., 1989, 26, 68, with a mixture of a carboxylate salt and the corresponding carboxylic acid, i.e., MOC(xe2x95x90O)Rxe2x80x2 and HOC(xe2x95x90O)Rxe2x80x2 mixture, such as sodium acetate/acetic acid and sodium pivalate/pivalic acid mixtures, in an aprotic organic solvent, preferably toluene. The mixture is heated at a temperature of about 80xc2x0 C. to about 120xc2x0 C., preferably about 100xc2x0 C. A typical reaction time is from about 15 hours to about 72 hours, preferably from about 20 hours to about 48 hours. The amount of carboxylate salt used can be about 2 equiv. to about 50 equiv., preferably about 2 equiv. to about 25 equiv., more preferably about 2.1 equiv. to about 10 equiv., and most preferably about 2.5 equiv. Preferably a small excess of [RuCl2(COD)]n is used relative to the diphosphine compound to ensure complete conversion of the diphosphine compound.
While commercially available [RuCl2(COD)]n complex can be used, it has been found that freshly prepared [RuCl2(COD)]n complex from ruthenium trichloride generally affords shorter reaction time, more consistant and/or higher yield of ruthenium dicarboxylate diphosphine compound. In this manner, a one-pot synthesis of ruthenium dicarboxylate diphosphine compound can be achieved from relatively inexpensive and readily available ruthenium trichloride.
The xcex2-hydroxy compound (e.g., 3-(R)-hydroxy compound) XIII can be further purified, i.e., enantiomerically enriched, by recrystallizing the initial product to afford a product having at least about 99 %ee. Therefore, it should be appreciated that depending on the cost of a particular chiral hydrogenation catalyst, it may be more economical to use a chiral hydrogenation catalyst which provides less than about 95 %ee of the xcex2-hydroxy compound XIII, which can be further enantiomerically enriched by recrystallization.
Unlike currently used ruthenium-based hydrogenation catalysts for asymmetric reduction of methyl 3-oxotetradecano-ate, the hydrogenation catalyst of the present invention does not require high purity conditions, e.g., hydrogen gas having purity of at least about 99.99%, to produce methyl 3-hydroxytetradecanoate in high yield and high enantiomeric excess. In fact, the asymmetric hydrogenation of methyl 3-oxotetradecanoate under technical grade conditions, e.g., hydrogen gas having purity of about 99.5% and nitrogen gas having purity of about 99.5%, using the hydrogenation catalyst of the present invention proceeds with a substantially similar rate as those requiring high purity reaction conditions. Moreover, the hydrogenation catalyst of the present invention allows the use of lower hydrogen gas pressure, thereby reducing the cost of initial capital investments and reducing the danger associated with high hydrogen gas pressure reaction conditions. In addition, by using asymmetric hydrogenation processes described above, the present invention allows asymmetric synthesis of the xcex4-lactone I without a need for resolving any racemic intermediates.
Typically, hydrogenation of xcex2-ketoester XVI, e.g., methyl 3-oxotetradecanoate, is conducted in a conventional hydrogenation solvent including an alkyl alcohol, such as ethanol or preferably in methanol, at a reaction temperature of about 80xc2x0 C. The concentration of the substrate (i.e., xcex2-ketoester XVI) in hydrogenation reaction is generally at about 40 wt %, and the ratio of HCl to Ru(OAc)2((R)-MeOBIPHEP) in the hydrogenation catalyst is about 20:1. A typical ratio of methyl 3-oxotetradecanoate to the hydrogenation catalyst is about 50,000:1. To this reaction mixture, typically about 40 bar of technical grade hydrogen gas is added, and the reaction is allowed to proceed for about 4 hours (h). The resulting methyl (R)-3-hydroxy tetradecanoate is then saponified by diluting the crude hydrogenation solution in methanol and 28% aqueous sodium hydroxide solution at room temperature. The saponified product is then acidified with an acid, such as sulfuric acid, to isolate (R)-3-hydroxy tetradecanoic acid. In this manner, the xcex2-hydroxy acid IIA, such as(R)-3-hydroxy tetradecanoic acid, can be produced in at least about 90% isolated yield from the corresponding xcex2-ketoester XVI, more preferably in at least about 93% isolated yield and most preferably in at least about 95% isolated yield. The enantiomeric excess of the product is at least about 90%ee, preferably at least about 95%ee, and more preferably at least about 99%ee. The enantiomeric excess can be increased to at least about 95%ee after a single recrystallization, preferably at least about 99%ee, and most preferably at least about 99.5%ee.
The xcex2-ketoester XVI can be readily prepared by a variety of known methods. See for example, Case-Green, Synlett, 1991, 781-782 and U.S. Pat. No. 5,945,559, issued to Sotoguchi et al., which are incorporated by reference herein in their entireties.
The xcex4-lactone I can also be prepared by treating a 2-alkyl-acetoacetate ester of the formula: 
with acyl halide IIA and contacting the resulting product with a base or preferably an acid, such as those described above, under conditions sufficeient to produce the xcex4-lactone I, wherein R2 and R5 are those described above.
Without being bound by any theory, it is believed that a reaction between the 2-alkyl-acetoacetate ester XVII and the acyl halide IIA produces xcex1-acetyl-xcex2-ketoester of the formula: 
as the initial product, where R1, R3 and R5 are those described above and R2 is C1-C10 alkyl. Solvolysis, e.g., methanolysis (i.e., contacting with methanol), in basic or preferably acidic conditions, of xcex1-acetyl-xcex2-ketoester XVIII removes the acyl group to produce the xcex4-hydroxy-xcex2-ketoester VIA, where R7 is R3, which can then be used to produce the xcex4-lactone I as described above. Preparation of xcex2-ketoesters from methyl acetoacetate is disclosed in Japanese Patent No. 10-53561, issued to Sotokuchi et al., which is incorporated by reference herein in its entirety.
The 2-alkyl-acetoacetate ester XVII can be prepared by forming an enolate of acetoacetate ester by contacting the acetoacetate ester with a base, such as calcium oxide or calcium hydroxide, in typically refluxing toluene followed by reacting the enolate with the acyl halide IIA.
Alternatively, the xcex4-hydroxy-xcex2-ketoester VIA (where R2 is C1-C10 alkyl, preferably hexyl), and hence ultimately the xcex4-lactone I, can be produced by reacting acetoacetate ester (compound XVII, where R2 is H) with acyl chloride IIA as described above to initially produce the xcex4-hydroxy-xcex2-ketoester VIA (where R2 is H). The xcex4-hydroxy-xcex2-ketoester VIA, where R2 is H, can be deprotonated with a base to produce a second enolate which can be reacted with an alkyl group containing a leaving group, such as those described above, e.g., hexyl bromide, to produce the xcex4-hydroxy-xcex2-ketoester VIA (where R2 is C1-C10 alkyl, e.g., hexyl). In generating the second enolate, a reverse addition, i.e., addition of the xcex4-hydroxy-xcex2-ketoester VIA (where R2 is H) to a solution containing a base, can be used, for example, to reduce the amount of elimination product which may result in the conventional addition step, i.e., addition of a base to a solution of the xcex4-hydroxy-xcex2-ketoester VIA.